The objective of the proposed research is to study the generation and mechanism of action of thyroid stimulators in health and disease. The major goal in performing these studies is to further understanding of the pathogenesis of Graves' disease. Particular emphasis will be placed on the possible role of prostaglandins as well as the role of thyroid-stimulating immunoglobulins (TSI) in the pathogenesis of Graves' disease. Immunoglobulin preparations from sera of patients with Graves' disease and normal subjects will be tested for their ability to stimulate cAMP generation in cultured human thyroid cells. It is planned to determine the incidence of TSI in patients with active Graves' disease and to relate this incidence to the state of the disease. Prostaglandins will be measured by radioimmunoassay in thyroid venous effluent and shunted, venous (near-arterial) blood of patients undergoing thyroid surgery. The objective of the study is to determine whether there is an increase in prostaglandin generation in the thyroid gland of patients with Graves' disease. The effect of indomethacin on the hyperthyroidism of patients with Graves' disease will be studied. Total or partial remission of the thyrotoxicosis would be evidence in support of a role for prostaglandins in the pathogenesis of this disease. Cellular and medium prostaglandin concentrations will be measured by radio-immunoassay during the culture of thyroid cells in monolayer. The effect of TSH, cAMP analogues and TSI on this process will be examined. Prostaglandin bioactivity in the medium, generated during the co-culture of human thyroid cells and human peripheral lymphocytes, will be correlated with medium and cellular prostaglandin concentrations as determined by radioimmunoassay.